1-243505296-G-C

Variant names:

• chr1-243505296-G-C
• rs587776935
• NM_005465.7:c.1393C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_005465.7(AKT3):​c.1393C>G​(p.Arg465Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59
• Publications: 0 publications found

Genes affected

AKT3 (HGNC:393): (AKT serine/threonine kinase 3) The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

AKT3 Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P
• megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae)
• megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microcephaly

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-243505296-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the AKT3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.946 (above the threshold of 3.09). Trascript score misZ: 4.2291 (above the threshold of 3.09). GenCC associations: The gene is linked to megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, microcephaly, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005465.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	NM_005465.7	MANE Select	c.1393C>G	p.Arg465Gly	missense	Exon 14 of 14	NP_005456.1
	AKT3	NM_001370074.1		c.1393C>G	p.Arg465Gly	missense	Exon 14 of 14	NP_001357003.1
	AKT3	NM_001206729.2		c.1355-5510C>G		intron	N/A	NP_001193658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT3	ENST00000673466.1	MANE Select	c.1393C>G	p.Arg465Gly	missense	Exon 14 of 14	ENSP00000500582.1
	AKT3	ENST00000263826.12	TSL:1	c.1393C>G	p.Arg465Gly	missense	Exon 14 of 14	ENSP00000263826.5
	AKT3	ENST00000336199.9	TSL:1	c.1355-5510C>G		intron	N/A	ENSP00000336943.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.27
Sift	Benign	0.057	T
Sift4G	Benign	0.24	T
Polyphen		0.020	B
Vest4		0.63
MutPred		0.47		Loss of stability (P = 0.0965)
MVP		0.87
MPC		2.7
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.82
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776935; hg19: chr1-243668598;